A cyclic xcex1-amino-xcex3-hydroxy acid compound has been described in the journal J. Org. Chem. 1994, 59 (26), 8101-6, without their having been any pharmacological activity mentioned for that compound.
In addition to the fact that they are new, the compounds of the present invention have valuable pharmacological properties. They have blood glucose-lowering properties, rendering them beneficial in the treatment of glucose intolerance and disorders associated with hyperglycaemia, such as type II diabetes or obesity.
The present invention relates more specifically to compounds of formula (I): 
wherein: 
represents a saturated carbon ring having from 4 to 8 ring members, optionally substituted by one or more linear or branched (C1-C6)alkyl groups,
R1 and R4, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)acyl group,
R2 and R3, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
R5 and R6, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
xe2x80x83or R5 and R6 together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle optionally substituted by one or more identical or different groups selected from the groups cyano, CO2R7 (wherein R7 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group), COR7 (wherein R7 is as defined hereinbefore), nitro, CONR8aR8b (wherein R8a and R8b, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)alkyl group or R8a and R8b together form a nitrogen-containing heterocycle), S(O)nR9 (wherein n represents 1, 2 or 3, and R9 represents a hydrogen atom, a linear or branched (C1-C6)-alkyl group or an aryl group) and PO3R10aR10b (wherein R10a and R10b, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)-alkyl group),
to stereoisomers thereof, and also to addition salts thereof with a pharmaceutically acceptable acid.
Amongst the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulphonic, benzenesulphonic, camphoric acid, etc.
A nitrogen-containing heterocycle is to be understood as an optionally bridged, saturated mono- or bi-cyclic group having from 5 to 12 ring members and containing one, two or three hetero atoms, one of those hetero atoms being the nitrogen atom and the additional hetero atom or atoms optionally present being selected from the atoms oxygen, nitrogen and sulphur. Preferred nitrogen-containing heterocycles are the groups pyrrolidinyl, thiazolidinyl, piperidyl, morpholinyl, azabicyclo[3.3.0]octyl and piperazinyl.
An aryl group is to be understood as phenyl, biphenylyl, naphthyl or tetrahydronaphthyl, each of those groups optionally being substituted by one or more identical or different atoms or groups selected from the halogen atoms and the groups linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)poly-haloalkyl, nitro and (C1-C2)alkylenedioxy.
Preferred compounds of formula (I) are those wherein 
represents a carbon ring having 5 or 6 ring members.
An advantageous variant of the invention concerns compounds of formula (I) wherein R5 and R6 together form an optionally substituted nitrogen-containing heterocycle. Among those, preference is given especially to such compounds in which R5 and R6 together form an optionally substituted pyrrolidine or an optionally substituted thiazolidine.
Amongst the preferred compounds of the invention, the following may be mentioned more especially:
(1R,2S,1xe2x80x2S)-2-[1xe2x80x2-amino-2xe2x80x2-oxo-2xe2x80x2-(1-pyrrolidinyl)ethyl]cyclohexanol, its (1S,2R,1xe2x80x2R) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid;
(1R*,2R*,1xe2x80x2R*)-2-[1xe2x80x2-amino-2xe2x80x2-oxo-2xe2x80x2-(1-pyrrolidinyl)ethyl]cyclopentanol, and also addition salts thereof with a pharmaceutically acceptable acid, wherein a (1R*,2R*,1xe2x80x2R*) compound is to be understood as a racemic mixture of the 2 enantiomers having the absolute configurations (1R,2R,1xe2x80x2R) and (1S,2S,1xe2x80x2S);
(1R,2S,1xe2x80x2R)-2-[1xe2x80x2-amino-2xe2x80x2-oxo-2xe2x80x2-(1-pyrrolidinyl)ethyl]cyclopentanol, its (1S, 2R,1xe2x80x2S) enantiomer, and also addition salts therof with a pharmaceutically aceptable acid;
(1R,2S,1xe2x80x2S)-2-[1xe2x80x2-amino-2xe2x80x2-oxo-2xe2x80x2-(1-pyrrolidinyl)ethyl]cyclopentanol, its (1S, 2R,1xe2x80x2R) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid;
(1R,2S,1xe2x80x2R)-2-[1xe2x80x2-amino-2xe2x80x2-oxo-2xe2x80x2-(1-pyrrolidinyl)ethyl]cyclohexanol, its (1S,2R,1xe2x80x2S) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid;
and (1R,2S,1xe2x80x2R)-2-[1xe2x80x2-amino-2xe2x80x2-oxo-2xe2x80x2-(1,3-thiazolidin-3-yl)ethyl]cyclohexanol, its (1S,2R,1xe2x80x2S) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid.
The invention extends also to a process for the preparation of compounds of formula (I), which process is characterised in that chloroacetyl chloride is reacted with a compound of formula (II):
HNR5R6xe2x80x83xe2x80x83(II) 
wherein R5 and R6 are as defined for formula (I),
to yield a compound of formula (III): 
wherein R5 and R6 are as defined hereinbefore,
which is converted into an amine of formula (IV): 
wherein R5 and R6 are as defined hereinbefore,
which is reacted with benzaldehyde to yield a compound of formula (V): 
wherein R5 and R6 are as defined hereinbefore,
which is reacted with a compound of formula (VI): 
wherein 
R2 and R3 are as defined for formula (I),
to yield, after optional acylation of the hydroxy function, a compound of formula (VII), which is of the relative configuration trans: 
wherein 
R1, R2, R3, R5 and R6 are as defined hereinbefore,
which is converted by hydrolysis followed, if desired, by acylation of the amino function, to yield a compound of formula (Ia) of the relative configuration trans, a particular case of the compounds of formula (I): 
wherein 
R1, R2, R3, R4, R5 and R6 are as defined hereinbefore,
which is converted, if desired, into a compound of formula (Ib) of the relative configuration cis, a particular case of the compounds of formula (I): 
wherein 
R1, R2, R3, R4, R5 and R6 are as defined hereinbefore,
which compounds of formulae (Ia) and (Ib) are separated, if desired, into their isomers by conventional separation techniques, are purified, if necessary, by conventional methods of purification, and are converted, if desired, into addition salts with a pharmaceutically acceptable acid.
The compounds of formula (Ic), a particular case of the compounds of formula (I): 
wherein 
represents a saturated carbon ring having 6 ring members optionally substituted by one or more linear or branched (C1-C6)alkyl groups, and R1, R2, R3, R4, R5 and R6 are as defined for formula (I),
can also be obtained from a compound of formula (VIII): 
wherein R11 represents a hydrogen atom or a phenyl group, and G represents CN or a linear or branched (C1-C6)alkoxycarbonyl group,
which is reacted with a compound of formula (VIa), a particular case of the compounds of formula (VI): 
wherein 
R2 and R3 are as defined hereinbefore,
to yield a compound of formula (IX) of the relative configuration trans: 
wherein 
G, R2, R3 and R11 are as defined hereinbefore,
which compound of formula (IX):
when it is desired to obtain a compound of the relative configuration trans, is hydrolysed under acid conditions to yield, after optional acylation of the amino function, a compound of formula (Xt) in which the ring junction is trans: 
wherein 
R2, R3 and R4 are as defined hereinbefore,
which is reacted with a compound of formula (II) to yield, after optional acylation of the hydroxy function, a compound of formula (Id) of the relative configuration trans, a particular case of the compounds of formula (Ic): 
wherein 
R1, R2, R3, R4, R5 and R6 are as defined hereinbefore,
or, when it is desired to obtain a compound of the relative configuration cis, is subjected to a Mitsunobu reaction to yield, after optional acylation of the amino function, a compound of formula (Xc) in which the ring junction is cis: 
wherein 
R2, R3 and R4 are as defined hereinbefore,
which is reacted with a compound of formula (II) to yield, after optional acylation of the hydroxy function, a compound of formula (Ie) of the relative configuration cis, a particular case of the compounds of formula (Ic): 
wherein 
R1, R2, R3, R4, R5 and R6 are as defined hereinbefore,
which compounds of formulae (Id) and (Ie) are separated, if desired, into their stereoisomers by conventional separation techniques, are purified, if necessary, by conventional methods of purification, and are converted, if desired, into addition salts with a phamaceutically acceptable acid.
The compounds of formula (If) of the relative configuration cis, a particular case of the compounds of formula (I): 
wherein 
represents a saturated carbon ring having 5 chain members optionally substituted by one or more groups selected from linear and branched (C1-C6)alkyl groups, and R1, R2, R3, R4, R5 and R6 are as defined for formula (I),
can also be obtained from a compound of formula (VIII), which is reacted with a compound of formula (VIb), a particular case of the compounds of formula (VI): 
wherein 
R2 and R3 are as defined hereinbefore,
to yield a compound of formula (XI) of the relative configuration trans: 
wherein 
R2, R3 and R11 are as defined hereinbefore,
which is hydrolysed under acid conditions to yield, after optional acylation of the amino function, a compound of formula (XII) in which the ring junction is cis: 
wherein 
R2, R3 and R4 are as defined hereinbefore,
which is reacted with a compound of formula (II) to yield, after optional acylation of the hydroxy function, a compound of formula (If), which is separated, if desired, into its stereoisomers by conventional separation techniques, is purified, if necessary, by conventional methods of purification and is converted, if desired, into addition salts with a pharmaceutically acceptable acid.
The compounds of formula (Ig) of the relative configuration trans, a particular case of the compounds of formula (I): 
can also be obtained from a compound of formula (XIII): 
wherein R11 is as defined hereinbefore, and R12 represents a linear or branched (C1-C6)alkyl group,
which is reacted with a compound of formula (VIb) to yield a compound of formula (XIV) of the relative configuration trans: 
wherein 
R2, R3, R11 and R12 are as defined hereinbefore,
which is hydrolysed under mild acid conditions to yield, after acylation or protection of the amino function, a compound of formula (XV) of the relative configuration trans: 
wherein 
R2, R3 and R12 are as defined hereinbefore, and Rxe2x80x24 represents either a linear or branched (C1-C6)alkyl group or an amino function-protecting group,
which compound of formula (XV) is reacted, under peptide coupling conditions, with a compound of formula (II) to yield, after optional acylation of the hydroxy function and optional deprotection of the amino function, a compound of formula (Ig), which is separated, if desired, into its stereoisomers by conventional separation techniques, is purified, if necessary, by conventional methods of purification and is converted, if desired, into addition salts with a pharmaceutically acceptable acid.
In addition to the fact that they are new, the compounds of the present invention have valuable pharmacological properties. They have blood glucose-lowering properties, rendering them beneficial in the treatment of glucose intolerance and disorders associated with hyperglycaemia, such as type II diabetes or obesity.
The invention extends also to pharmaceutical compositions comprising as active intredient at least one compound of formula (I) with one or more appropriate, inert, non-toxic excipients. Amongst the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions, etc.
The useful dosage is adaptable in accordance with the nature and severity of the disorder, the administration route and also the age and weight of the patient and any associated treatments. The dosage ranges from 0.5 mg to 2 g per 24 hours in one or more administrations.
The Examples which follow illustrate the invention but do not limit it in any way.
The starting materials used are known products or products prepared according to known preparation procedures.
The structures of the compounds described in the Examples were determined according to customary spectrometric techniques (infra-red, NMR, mass spectrometry).
A (1R*,2R*,1xe2x80x2S*) compound is to be understood as a racemic mixture of the 2 enantiomers having the absolute configurations (1R,2R,1xe2x80x2S) and (1S,2S,1xe2x80x2R).
A (1R*,2R*,1xe2x80x2RS) compound is to be understood as a mixture of the 4 stereoisomers having the absolute configurations (1R,2R,1xe2x80x2R), (1R,2R,1xe2x80x2S), (1S,2S,1xe2x80x2R) and (1S,2S,1xe2x80x2S).
A compound having a (1xcex1,2xcex2,1xe2x80x2xcex2) or (1xcex2,2xcex1,1xe2x80x2xcex1) configuration is to be understood as a compound selected from the compounds having the absolute configurations (1R,2S,1xe2x80x2S) and (1S,2R,1xe2x80x2R), wherein when the (1xcex1,2xcex2,1xe2x80x2xcex2) compound represents the compound having the (1R,2S,1xe2x80x2S) configuration, then the (1xcex2,2xcex1,1xe2x80x2xcex1) compound represents the other enantiomer.
A fumarate of a compound is to be understood as a 1:1 addition salt of the said compound with fumaric acid (1 mol of fumaric acid per mol of compound). A hemifumarate of a compound is to be understood as a 1:0.5 addition salt of the said compound with fumaric acid (0.5 mol of fumaric acid per mol of compound).